TY - JOUR
T1 - Pediatric Cytochrome P450 Activity Alterations in Nonalcoholic Steatohepatitis
JF - Drug Metabolism and Disposition
JO - Drug Metab Dispos
M3 - 10.1124/dmd.117.077644
AU - Li, Hui
AU - Mark, Canet J
AU - Clarke, John D
AU - Billheimer, Dean
AU - Xanthakos, Stavra A
AU - Lavine, Joel E
AU - Erickson, Robert P
AU - Cherrington, Nathan J
Y1 - 2017/01/01
UR - http://dmd.aspetjournals.org/content/early/2017/10/06/dmd.117.077644.abstract
N2 - Variable drug responses(VDRs) are dependent upon individual variation in the activity of drug-metabolizing enzymes including cytochrome P450s(CYPs). As the most common chronic liver disease in children and adults, nonalcoholic steatohepatitis(NASH) has been identified as a source of significant inter-individual variation in hepatic drug metabolism. Compared to adults, children present age-related differences in pharmacokinetics and pharmacodynamics. The purpose of this study was to determine the impact of fatty liver disease severity on the activity of a variety of CYPs in children and adolescents. Healthy and nonalcoholic fatty liver disease(NAFLD) pediatric subjects ages 12-21 years inclusive received an oral cocktail of four probe drugs: caffeine(CYP1A2,100mg), omeprazole(CYP2C19,20mg), losartan(CYP2C9,25mg), and midazolam(CYP3A4,2mg). Venous blood and urine were collected pre-administration and 1, 2, 4 and 6h post-administration. Concentrations of parent drugs and CYP-specific metabolites were quantified in plasma and urine using LC-MS/MS. In plasma, decreased metabolic area under the curve(AUC) ratio, defined as metabolite AUC to parent AUC, of omeprazole indicated significant decreases of CYP2C19(p=0.002) enzymatic activities in NASH adolescents, while the urine analyses didn't show significant differences and were highly variable. A comparison between the present in vivo pediatric studies and a previous ex vivo study in adult indicates distinct differences in the activities of CYP1A2 and CYP2C9. These data demonstrate that pediatric NASH presents an altered pattern of CYP activity and NASH should be considered as a confounder of drug metabolism for certain CYPs. These differences could lead to future investigations that may reveal unexpected VDRs that should be considered in pediatric dosage recommendations.
ER -